Fibromyalgia and associated conditions such as
irritable bowel syndrome and
temporomandibular disorder involve dysfunctions in central sensitization and
pain modulation. Central nervous system dysfunction may also contribute to other symptoms characteristic of
fibromyalgia, such as
fatigue and sleep disturbance. Two key
neurotransmitters in the
pain modulation pathway are
serotonin and
norepinephrine. Preclinical studies using animal models of
chronic pain have shown that pharmacologic agents that combine serotonergic and noradrenergic reuptake inhibition, thus augmenting the function of these
neurotransmitters, have stronger
analgesic effects than agents that inhibit reuptake of either
neurotransmitter alone. Although
tricyclic antidepressants (TCAs) inhibit reuptake of both
serotonin and
norepinephrine and have shown efficacy for the treatment of
fibromyalgia, long-term use of these drugs is limited owing to poor tolerability. Unlike TCAs, the newer dual reuptake inhibitors of
serotonin and
norepinephrine, such as the drugs approved by the US Food and Drug Administration (FDA) for
fibromyalgia,
milnacipran and
duloxetine, do not possess significant affinity for other
neurotransmitter systems, resulting in diminished side effects and enhanced tolerability. Both
duloxetine and
milnacipran have shown efficacy in clinical trials by improving
pain and other symptoms associated with
fibromyalgia. Both compounds inhibit the
serotonin and
norepinephrine transporters; however, there is a difference in their affinities and selectivity for these transporters. Although
duloxetine has affinity for both receptors, it is somewhat more selective for the
serotonin transporter. In contrast,
milnacipran is somewhat more selective for
norepinephrine than
serotonin reuptake inhibition. Pharmacologic agents that specifically target
serotonin and
norepinephrine reuptake may prove to be valuable tools in the treatment of
fibromyalgia.